The Na,K-ATPase is a ubiquitous plasma membrane ion transporter, in fact, the first enzyme recognized to be an ion pump. It uses the hydrolysis of one molecule of ATP to drive the coupled transport of three sodium ions out of the cell and two potassium ions into the cell. Its activity is essential for maintaining membrane ion gradients responsible for membrane potential by clearing potassium from the extracellular space and removing excess sodium from the intracellular space. Cardiac glycosides, such as ouabain and strophanthidin, which are used to treat some forms of cardiac disease, produce some or all of their effects by blocking the pumping activity of the Na,K-ATPase.
Na,K-ATPase is a member of the family of P-type ATPases. It is a heterodimeric integral membrane protein, consisting of one α and one β subunit. The α subunit, an ˜100 kDa protein with 10 predicted membrane spans, is the catalytic subunit responsible for ion translocation and ATPase activity. The β subunit, a 50-60 kDa glycosylated protein with a single membrane-spanning domain, may act as a molecular chaperone or otherwise regulate the membrane targeting and/or function of the α subunit. At least four distinct α subunit and three β subunit isoforms have been identified, and there appears to be no preferential association of particular α subunits with particular β subunits.
Relatively little is known about the endogenous regulation of Na,K-ATPase. Catecholamines (Phillis, J. W., Cell, Tissue and Organ Cultures in Neurobiology, pp. 93-97 (1978); Horwitz, B. A., Fed. proc., 38:2170-2176 (1979)), thyroid hormone (Smith, T. J. and I. S. Edelman, Fed. Proc., 38:2150-2153 (1979)), aldosterone (Rossier, B. C., et al., Science, 12:483-487 (1987)), linoleic and linolenic acids (Bidard, J. N., et al., Biochem. Biophys. Acta., 769:245 (1984); Tamura, M., et al., J. Biol. Chem., 260:9672 (1985); and vanadium (Cantley, L. C., Jr., et al., J. Biol. Chem., 243:7361-7368 (1978)) have all been linked to either direct or indirect effects on enzyme activity.
There are several neurological diseases or disorders in which there has been reported a change in Na pump function, such as familial hemiplegic migraine, cardiac disease, end-stage kidney disease, neuropathy, and others. Therefore, a modulator of Na,K-ATPase is highly desirable for its potential as a drug for treating these disorders or diseases